Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition

ABSTRACT

The invention provides new triazolo[4,5-d]pyrimidine compounds, their use as medicaments, compositions containing them and processes for their preparation.

FIELD OF THE INVENTION

The present invention provides new triazolo[4,5-d]pyrimidine compounds,their use as medicaments, compositions containing them and processes fortheir preparation.

BACKGROUND OF THE INVENTION

to Platelet adhesion and aggregation are initiating events in arterialthrombosis. Although the process of platelet adhesion to thesub-endothelial surface may have an important role to play in the repairof damaged vessel walls, the platelet aggregation that this initiatescan precipitate acute thrombotic occlusion of vital vascular beds,leading to events with high morbidity such as myocardial infarction andunstable angina. The success of interventions is used to prevent oralleviate these conditions, such as thrombolysis and angioplasty is alsocompromised by platelet mediated occlusion or re-occlusion.

A number of converging pathways lead to platelet aggregation. Whateverthe initial stimulus, the final common event is a cross-linking ofplatelets by binding of fibrinogen to a membrane-binding site,glycoprotein IIb/IIIa (GPIIb/IIIa). The high anti-platelet efficacy ofantibodies or antagonists for GPIIb/IIIa is explained by theirinterference with this final common event. However, this efficacy mayalso explain the bleeding problems that have been observed with thisclass of agent. Thrombin can produce platelet aggregation largelyindependently of other pathways but substantial quantities of thrombinare unlikely to be present without prior activation of platelets byother mechanisms. Thrombin inhibitors such as hirudin are highlyeffective anti-thrombotic agents, but again may produce excessivebleeding because they function as both anti-platelet and anti-coagulantagents (The TIMI 9a Investigators (1994), Circulation 90, pp. 1624-1630;The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)Ea Investigators (1994) Circulation 90, pp. 1631-1637; Neuhaus K. L. et.al. (1994) Circulation 90, pp. 1638-1642).

It has been found that adenosine 5′-diphosphate (ADP) acts as a keymediator of thrombosis. A pivotal role for ADP is supported by the factthat other agents, such as adrenaline and 5-hydroxytryptamine (5HT,serotonin) will only produce aggregation in the presence of ADP. Thelimited anti-thrombotic efficacy of aspirin may reflect the fact that itblocks only one source of ADP which is that released in athromboxane-dependent manner following platelet adhesion (see e.g.Antiplatelet Trialists' Collaboration (1994), Br. Med. J. 308, pp.81-106 and Antiplatelet Trialists' Collaboration (1994), Br. Med. J.308, pp. 159-168). Aspirin has no effect on aggregation produced byother sources of ADP, such as damaged cells or ADP released underconditions of turbulent blood flow.

ADP-induced platelet aggregation is mediated by the P_(2T) receptorsubtype located on the platelet membrane. The P_(2T) receptor (alsoknown as P2Y_(ADP) or P2T_(AC)) is primarily involved in mediatingplatelet aggregation/activation and is a G-protein coupled receptorwhich is as yet uncloned. The pharmacological characteristics of thisreceptor have been described, for example, in the references byHumphries et al., Br. J. Pharmacology (1994), 113, 1057-1063, and Faguraet al., Br. J. Pharmacology (1998) 124, 157-164. Recently it has beenshown that antagonists at this receptor offer significant improvementsover other anti-thrombotic agents (see J. Med. Chem. (1999) 42, 213).Accordingly there is a need to find further P_(2T) (P2Y_(ADP) orP2T_(AC)) antagonists as anti-thrombotic agents.

International Patent Application WO 9905143 discloses generically aseries of triazolo[4,5-d]-pyrimidine compounds having activity as P_(2T)(P2Y_(ADP) or P2T_(AC)) antagonists. It has now been found that certaincompounds within the scope of International Patent Application WO9905143 but not specifically disclosed therein exhibit high potencycombined with surprisingly high metabolic stability and bioavailibility,such that the predicted therapeutic dose for prolonged inhibition ofaggregation in man shows advantage.

DESCRIPTION OF THE INVENTION

In a first aspect the invention therefore provides a compound of formula(I):

wherein:

R¹ is C₃₋₅ alkyl optionally substituted by one or more halogen atoms;

R² is a phenyl group, optionally substituted by one or more fluorineatoms;

R³ and R⁴ are both hydroxy;

R is XOH, where X is CH₂, OCH₂CH₂ or a bond;

or a pharmaceutically acceptable salt or solvate thereof, or a solvateof such a salt.

provided that:

when X is CH₂ or a bond, R¹ is not propyl.

when X is CH₂ and R¹ is CH₂CH₂CF₃, butyl or pentyl, the phenyl group atR² must be substituted by fluorine.

when X is OCH₂CH₂ and R¹ is propyl, the phenyl group at R² must besubstituted by fluorine.

Alkyl groups, whether alone or as part of another group are straightchained and fully saturated.

Suitably R¹ is a C₃₋₅ alkyl optionally substituted by one or morefluorine atoms. Preferably R¹ is C₃₋₅ alkyl optionally substituted onthe terminal carbon by three fluorine atoms. More preferably R¹ is3,3,3,-trifluoropropyl, butyl or propyl.

Suitably R² is phenyl or phenyl substituted by one or more fluorineatoms. Preferably R² is phenyl, 4-fluorophenyl or 3,4-difluorophenyl.

Suitably R is XOH where X is CH₂, OCH₂CH₂ or a bond.

Preferably R is CH₂OH or OCH₂CH₂ OH.

Particularly preferred compounds include:

-   [1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol:-   [1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]primidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;-   [1S-(1α,2α,3β(1S*,2R*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;-   [1S-(1α,2α,3β(1R*,2S*),5β]]-3-[5-Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;-   [1S-(1α,2α,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(4-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2,3-triol;-   [1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[(2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;-   [1S-[1α,2α,3β,5β(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-(2-phenylcyclopropyl)amino]5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol-   [1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Burylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-trial;-   [1S-[1α,2α,3β(1S*,2R*),5β]]-3-[5-(Butylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;    and pharmaceutically acceptable salts or solvates thereof, or    solvates of such salts.

According to the invention there is further provided a process for thepreparation of a compound of formula (I) which comprises:

(a) reacting a compound of formula (II):

where R, R¹, R³ and R⁴ are as defined in formula (I), or are protectedderivatives thereof, or R³ and R⁴ together form a bond in the 5-memberedring, or R is CH₂CH₂ OR′, where R′ is C₁₋₆ alkyl or benzyl, and L is aleaving group such as halogen or SR, with a compound of to formula (II):

where R² is as defined in formula (I), or is a protected derivativethereof,or where X is a bond:(b) hydroxylation of a compound of formula (IV):

where R¹ is defined in formula (I) and R⁸ is H or CH₂CH₂OP³ where P³ isH or a protecting group or R⁸ is CH₂COOR′ where R′ is C₁₋₆ alkyl orbenzyl, and Z is NH₂ or

where R² is defined in formula (I).and for both (a) and (b) optionally thereafter and in any order:converting one or more functional groups into further functional groups;removing any protecting groups;forming a pharmaceutically acceptable salt or solvate, or a solvate ofsuch a salt.

Compounds of formula (II) can be reacted with amines of formula (III) inthe presence of a base, such as a tertiary organic amine, in an inertsolvent, such as dichloromethane, at ambient or elevated temperature.Other suitable bases include inorganic bases such as potassiumcarbonate.

The hydroxy groups R³ and R⁴ can be protected as groups OP¹ and OP²where P¹ and P² are protecting groups. Examples of suitable protectinggroups in compounds of formula (II) are C₁₋₆alkyl (preferably methyl),benzyl, (C₁₋₆alkyl)₃Si (preferably t-butyldimethylsilyl), and aC(O)C₁₋₆alkyl group such as acetyl. Preferably the two groups P¹ and P²together with the atoms to which they are attached form an alkylidenering such as a methylidene or isopropylidene ring. Alternatively P¹ andP² can form an alkoxymethylidene ring such as ethoxymethylidene.

Protecting groups can be added and removed using known reactionconditions. The use of protecting groups is fully described in‘Protective Groups in Organic Chemistry’, edited by J W F McOmie. PlenumPress (1973), and ‘Protective Groups in Organic Synthesis’. 2nd edition,T W Greene & P G M Wutz, Wiley-Interscience (1991).

Ester protecting groups can be removed by basic hydrolysis, for exampleby using a metal hydroxide, preferably an alkali metal hydroxide, suchas sodium hydroxide or lithium hydroxide, or quaternary ammoniumhydroxide in a solvent, such as aqueous ethanol or aqueoustetrahydrofuran, at a temperature of from 10° to 100° C., preferably thetemperature is around room temperature: or by acidic hydrolysis using amineral acid such as HCl or a strong organic acid such astrichloroacetic acid in a solvent such as aqueous 1,4-dioxane.Trialkylsilyl protecting groups can be removed by the use of, forexample, a fluoride ion source, for example tetra-n-butylammoniumfluoride or hydrogen fluoride. When one or is both of P¹ and P² are C₁₋₆alkyl, deprotection can be achieved using boron tribromide. Benzylgroups can be removed by hydrogenolysis using a transition metalcatalyst, for example palladium on charcoal, under an atmosphere ofhydrogen, at a pressure of from 1 to 5 bar, in a solvent, such as aceticacid.

A compound of formula (II) can be prepared by diazotising a compound offormula (V):

wherein R¹ is as defined in formula (I), and R is as defined in formula(I), or is a protected derivative thereof, or is OCH₂CO₂R′, where R′ isC₁₋₆ alkyl or benzyl, and L is as defined above and R³ and R⁴ are asdefined in formula (I) or are protected derivatives thereof or R³ and R⁴together form a bond in the 5-membered ring,with a metal nitrite, for example an alkali metal nitrite, especiallysodium nitrite in dilute aqueous acid, for example 2M HCl, or with aC₁₋₆-alkyl nitrite, in an inert solvent, at a temperature of from about−20 to about 100° C. Preferred conditions are isoamyl nitrite inacetonitrile at about 80° C.

A compound of formula (V) wherein R is CH₂OH, R³ and R⁴ are hydroxyl orprotected derivatives thereof and L is as defined above, can be preparedby reducing a compound of to formula (VI):

wherein R¹, L, P¹ and P² are as defined above.

The reduction of the nitro group can be carried out for example by usinghydrogenation with a transition metal catalyst at a temperature aroundroom temperature, for example palladium on charcoal under an atmosphereof hydrogen, preferably at a pressure from 1 to atmospheres, in asolvent, for example ethanol, or by using iron in an acidic solvent suchas acetic acid at a temperature of about 100° C.

Reduction of the lactam can be carried out using complex metal hydridessuch as lithium aluminium hydride in a solvent such as ether orpreferably, by using sodium borohydride in a suitable solvent such asmethanol.

A compound of formula (VI) can be prepared by reacting a compound offormula (VII):

wherein L and R¹ are as defined above and L¹ is a leaving group, forexample a halogen atom, wherein L and L¹ are preferably the same, with acompound of formula (VIII):

wherein P¹ and P² are as defined above, in the presence of a base suchas C₁₋₆-alkyl-M or MH wherein M is a metal ion, for example n-butyllithium, in an inert solvent, such as tetrahydrofuran, at a temperatureof from about −10 to about 100° C. Preferably sodium hydride is used intetrahydrofuran at room temperature.

One or more functional groups can be converted into further functionalgroups using standard chemistry. A compound where X is a bond can beconverted to a compound where X is O(CH₂): by treatment with basefollowed by LY where L is a leaving group and Y is (CH₂)₂OH or aprotected version thereof or Y is CH₂COOR′ where R′ is C₁₋₆alkyl orbenzyl. A compound where R is CH₂CH₂ OR may be converted into a compoundwhere R is O(CH₂)₂OH by reduction, for example using DIBAL-H®. The groupSR¹ can be interconverted by oxidation of the sulfur, for example usingOxone™ or mCBPA, followed by treatment with a compound R^(1′)—SM whereR^(1′) is a different R¹ group and M is a metal such as sodium.Alternatively the product of the sulfur oxidation may be treated withMSH where M is a metal such as sodium, followed by treatment with a baseand R^(1′)X where R^(1′) is a different R¹ group and X is a leavinggroup. Suitable bases include N,N-diisopropylethylamine.

A compound of formula (II) where R, R¹, R³, and R⁴ are as defined informula (I) or are protected derivatives thereof, or R³ and R⁴ togetherform a bond in the 5-membered ring, or R is OCH₂CO₂R′ where R′ is C₁₋₆alkyl or benzyl, and L is a leaving group such as halogen, may beconverted into a compound of formula (II) where R, R¹, R³, and R⁴ aredefined above and L is NH₂ by treatment with a diazotizing agent in thepresence of a halogenating agent, preferably isoamyl-nitrite and carbontetrabromide.

A compound of formula (II) where R, R¹, R³, and R⁴ are defined above andL is NH₂ may be prepared by treating a compound of formula (II) where R,R¹, R³, and R⁴ are as defined above and L is a leaving group such ashalogen, with ammonia in a solvent such as methanol.

Compounds of formula (V) can also be prepared by treating a compound offormula (XI)

where R, R³ and R⁴ are as defined in formula (I) or are protectedderivatives thereof or R is OCH₂CO₂R′ where R′ is C₁₋₆ alkyl or benzyl,or R³ and R⁴ together form a bond in the 5-membered ring,with a compound of formula (VII) as defined above, followed by reductionof the nitro group. The reaction is carried out in an inert solvent suchas dichloromethane or 1,4-dioxane, in the presence of a non-nucleophilicbase, such as N,N-diisopropylamine, at a temperature of about −20° C. toabout 150° C., preferably at ambient temperature.

Compounds of formula (II) where R is as defined in formula (I), R³ andR⁴ together form a bond in the 5-membered ring, and L is SR¹, or aprotected derivative thereof, can be prepared by reacting a compound offormula (XII):

where R¹ groups are as defined in formula (I),with a compound of formula (XIII):

in which R⁷ is H or a protected derivative thereof. The reaction can becarried out in the presence of a suitable transition metal complex,preferably tetrakistriphenylphosphine is palladium(0).

Compounds of formula (XII) can be prepared from compounds of formula(XIV):

by reacting with a compound R¹X where R¹ is as defined in formula (I)and X is a leaving group such as halo, followed by cyclisation.

Compounds of formula (XI) where R is OH or a protected version thereofand R³ and R⁴ are as defined in formula (I) or are protected derivativesthereof may be prepared from compounds of formula (XIII) where R⁷ is Hor a protecting group by treatment with a bisester of imidodicarbamicacid using palladium catalysis followed by hydroxylation of the doublebond, and optionally, deprotection of the nitrogen. Preferablyimidodicarbonic acid, bis-(1,1-dimethylethyl)ester andtetrakistriphenylphosphine palladium(0) are used followed by osmiumterroxide and deprotection using hydrochloric acid in methanol.

Compounds of formula (XI), where R is OCH₂CO₂R′ where R′ is C₁₋₆alkyland R³ and R⁴ together form a bond in the 5-membered ring, may be formedfrom compounds of formula (XIII), where R⁷ is H or a protecting group,by treatment with an azide in the presence of a palladium catalyst,followed by reduction of the azide and alkylation of the alcohol asdescribed previously.

Compounds of formula (XI) where R is OCH₂CH₂ OH and R³ and R⁴ are asdefined in formula (I) or are protected derivatives thereof may beprepared from compounds of formula (XI) where R is OH and R³ and R⁴ areas defined in formula (I) or are protected derivatives thereof, byprotection of the nitrogen, alkylation of the alcohol using a2-halo-acetic acid ester, followed by reduction of the ester anddeprotection of the nitrogen. We prefer protection of the nitrogen as acarbobenzyloxy derivative using benzyl chloroformate followed byalkylation of the alcohol using ethyl bromoacetate and potassiumt-butoxide, reduction of the ester using lithiumm borohydride intetrahydrofuran and deprotection of the nitrogen by hydrogenation in thepresence of palladium on carbon. In addition we prefer the case wherethe alcohols R³ and R⁴ are protected as an isopropylidene ring.

The amines of formula (III) can be prepared using procedures describedin H Nishiyama et al, Bull. Chem. Soc., Jpn., 1995, 68, 1247, P. Newman,Optical Resolution Procedures for Chemical Compounds, Vol. 1. Amines andRelated Compounds: Optical Resolution and Information Centre ManhattanCollege, Riverdale, N.Y., 1978, p 120, J. Vallgarda et al, J. Chem. Soc.Perkin 1, 1994, 461 or in International Patent Application WO 9905143.

All novel intermediates form a further aspect of the invention.

Salts of the compounds of formula (I) may be formed by reacting the freeacid, or a salt thereof, or the free base, or a salt or a derivativethereof, with one or more equivalents of the appropriate base (forexample ammonium hydroxide optionally substituted by C₁₋₆-alkyl or analkali metal or alkaline earth metal hydroxide) or acid (for example ahydrohalic (especially HCl), sulphuric, oxalic or phosphoric acid). Thereaction may be carried out in a solvent or medium in which the salt isinsoluble or in a solvent in which the salt is soluble, e.g. water,ethanol, tetrahydrofuran or diethyl ether, which may be removed invacuo, or by freeze drying. The reaction may also be a metatheticalprocess or it may be carried out on an ion exchange resin. The non-toxicphysiologically acceptable salts are preferred, although other salts maybe useful, e.g. in isolating or purifying the product.

The compounds of the invention act as P_(2T) (P2Y_(ADP) or P2T_(AC))receptor antagonists. Accordingly, the compounds are useful in therapy,including combination therapy, particularly they are indicated for useas: inhibitors of platelet activation, aggregation and degranulation,promoters of platelet disaggregation, anti-thrombotic agents or in thetreatment or prophylaxis of unstable angina, primary arterial thromboticcomplications of atherosclerosis such as thrombotic or embolic stroke,transient ischaemic attacks, peripheral vascular disease, myocardialinfarction with or without thrombolysis, arterial complications due tointerventions in atherosclerotic disease such as angioplasty, includingcoronary angioplasty (PTCA), endarterectomy, stent placement, coronaryand other vascular graft surgery, thrombotic complications of surgicalor mechanical damage such as tissue salvage following accidental orsurgical trauma, reconstructive surgery including skin and muscle flaps,conditions with a diffuse thrombotic/platelet consumption component suchas disseminated intravascular coagulation, thrombotic thrombocytopaenicpurpura, haemolytic uraemic syndrome, thrombotic complications ofsepticaemia, adult respiratory distress syndrome, anti-phospholipidsyndrome, heparin-induced thrombocytopaenia and pre-eclampsialeclampsia,or venous thrombosis such as deep vein thrombosis, venoocclusivedisease, haematological conditions such as myeloproliferative disease,including thrombocythaemia, sickle cell disease; or in the prevention ofmechanically-induced platelet activation in vivo, such ascardio-pulmonary bypass and extracorporeal membrane oxygenation(prevention of microthromboembolism), mechanically-induced plateletactivation in vitro, such as use in the preservation of blood products,e.g. platelet concentrates, or shunt occlusion such as in renal dialysisand plasmapheresis, thrombosis secondary to vascular damage/inflammationsuch as vasculitis, arteritis, glomerulonephritis, inflammatory boweldisease and organ graft rejection, conditions such as migraine.Raynaud's phenomenon, conditions in which platelets can contribute tothe underlying inflammatory disease process in the vascular wall such asatheromatous plaque formation/progression, stenosis/restenosis and inother inflammatory conditions such as asthma, in which platelets andplatelet-derived factors are implicated in the immunological diseaseprocess. Further indications include treatment of CNS disorders andprevention of the growth and spread of tumours.

According to the invention there is further provided the use of acompound according to the invention as an active ingredient in themanufacture of a medicament for use in the treatment or prevention ofthe above disorders. In particular the compounds of the invention areuseful for treating myocardial infarction, thrombotic stroke, transientischaemic attacks, peripheral vascular disease and stable and unstableangina, especially unstable angina. The invention also provides a methodof treatment or prevention of the above disorders which comprisesadministering to a person suffering from or susceptible to such adisorder a therapeutically effective amount of a compound according tothe invention.

The compounds may be administered topically, e.g. to the lung and/or theairways, in the form of solutions, suspensions, HFA aerosols and drypowder formulations; or systemically, e.g. by oral administration in theform of tablets, pills, capsules, syrups, powders or granules, or byparenteral administration in the form of sterile parenteral solutions orsuspensions, by subcutaneous administration, or by rectal administrationin the form of suppositories or transdermally.

The compounds of the invention may be administered on their own or as apharmaceutical composition comprising the compound of the invention incombination with a pharmaceutically acceptable diluent, adjuvant and/orcarrier. Particularly preferred are compositions not containing materialcapable of causing an adverse, e.g. an allergic, reaction.

Dry powder formulations and pressurised HFA aerosols of the compounds ofthe invention may be administered by oral or nasal inhalation. Forinhalation the compound is desirably finely divided. The compounds ofthe invention may also be administered by means of a dry powder inhaler.The inhaler may be a single or a multi dose inhaler, and may be a breathactuated dry powder inhaler.

One possibility is to mix the finely divided compound with a carriersubstance, e.g. a mono-, di- or polysaccharide, a sugar alcohol oranother polyol. Suitable carriers include sugars and starch.Alternatively the finely divided compound may be coated by anothersubstance. The powder mixture may also be dispensed into hard gelatinecapsules, each containing the desired dose of the active compound.

Another possibility is to process the finely divided powder into sphereswhich break up during the inhalation procedure. This spheronized powdermay be filled into the drug reservoir of a multidose inhaler, e.g. thatknown as the Turbuhaler® in which a dosing unit meters the desired dosewhich is then inhaled by the patient. With this system the active ascompound with or without a carrier substance is delivered to thepatient.

The pharmaceutical composition comprising the compound of the inventionmay conveniently be tablets, pills, capsules, syrups, powders orgranules for oral administration; sterile parenteral or subcutaneoussolutions, suspensions for parenteral administration or suppositoriesfor rectal administration.

For oral administration the active compound may be admixed with anadjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol,starches such as potato starch, corn starch or amylopectin, cellulosederivatives, a binder such as gelatine or polyvinylpyrrolidone, and alubricant such as magnesium stearate, calcium stearate, polyethyleneglycol, waxes, paraffin, and the like, and then compressed into tablets.If coated tablets are required, the cores, prepared as described above,may be coated with a concentrated sugar solution which may contain e.g.gum arabic, gelatine, talcum, titanium dioxide, and the like.Alternatively, the tablet may be coated with a suitable polymerdissolved either in a readily volatile organic solvent or an aqueoussolvent.

For the preparation of soft gelatine capsules, the compound may beadmixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatinecapsules may contain granules of the compound using either the abovementioned excipients for tablets, e.g. lactose, saccharose, sorbitol,mannitol, starches, cellulose derivatives or gelatine. Also liquid orsemisolid is formulations of the drug may be filled into hard gelatinecapsules.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example solutions containing the compound, the balancebeing sugar and a mixture of ethanol, water, glycerol and propyleneglycol. Optionally such liquid preparations may contain colouringagents, flavouring agents, saccharine and carboxymethylcellulose as athickening agent or other excipients known to those skilled in art.

EXAMPLES

The invention is illustrated by the following non-limiting examples.

In the examples the NMR spectra were measured on a Varian Unity Inova300 or 400 spectrometer and the MS spectra were measured as follows: EIspectra were obtained on a VG 70-250S or Finnigan Mat Incos-XLspectrometer, FAB spectra were obtained on a VG70-250SEQ spectrometer.ESt and APCI spectra were obtained on Finnigan Mat SSQ7000 or aMicromass Platform spectrometer. Preparative HPLC separations weregenerally performed using a Novapak®, Bondapak® or Hypersil® columnpacked with BDSC-18 reverse phase silica. Flash chromatography(indicated in the Examples as (SiO₂)) was carried out using FisherMatrix silica, 35-70 μm. For examples which showed the presence ofrotamers in the proton NMR spectra only the chemical shifts of the majorrotamer are quoted.

Example 1[1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diola)[3aS-[1(E),3aα,6α,7aβ]]-1-[3-(4-Fluorophenyl)-1-oxo-2-propenyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

A mixture of 3-(4-fluorophenyl)-2-propenoic acid (3.0 g) and thionylchloride (5.0 ml) was stirred at 70° C. for 1 hour, the reaction mixturewas then concentrated under reduced pressure. The residue was azeotropedtwice with dichloromethane then dissolved in toluene (10 ml). To asuspension of sodium hydride (60% dispersion in oil; 0.99 g) in toluene(40 ml) was added a solution of[3aS-(3aα,6α,7aβ)]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide(3.89 g) in toluene (40 ml) and the mixture stirred for 30 minutes. Tothe reaction mixture was then added the solution described above and theresulting suspension was stirred for 16 hours. Water (200 ml) was added,the organics collected and the aqueous extracted into dichloromethane(3×100 ml). The organics were combined, dried and concentrated.Recrystallisation (ethanol) gave the subtitle compound as colourlessneedles (5.92 g).

MS (APCI) 364 (M+H⁺, 100%)

b)[3aS-[1(1S*,2S*),3aα,6α,7aβ]]-1-[[2-(4-Fluorophenyl)cyclopropyl]carbonyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

A solution of diazomethane (2.9 g) in ether (150 ml) (prepared asdescribed in Vogel's Textbook of Practical Organic Chemistry, FifthEdition, Longman Scientific and Technical, p 432) was added to asolution of the product of step a) (5.90 g) and palladium(II) acetate(18 mg) in dichloromethane (350 ml) at 0° C. and the reaction mixturestirred at 0° C. for 5 hours. Acetic acid (5 ml) was added and thereaction mixture was then washed with saturated sodium bicarbonatesolution (200 ml) and the organics filtered through a plug of silica.After concentrating in vacuo, the residue was recrystallised (ethanol)to give the subtitle compound as colourless needles (3.81 g).

MS (APCI) 378 (M+H⁺, 100%)

c) (1R-trans)-2-(4-Fluorophenyl)-cyclopropanecarboxylic acid

A suspension of the product from step b) (3.74 g) and lithium hydroxidemonohydrate (4.11 g) in tetrahydrofuran (100 ml)/water (3 ml) wasstirred at 50° C. for 24 hours. The reaction mixture was concentrated invacuo, and the residue dissolved in water (100 ml), acidified with 2NHCl and extracted into dichloromethane (3×75 ml). The organics weredried and concentrated. Purification (SiO₂, isohexane:diethylether 2:1as eluant) gave the subtitle compound as a colourless solid (1.78 g).

MS (APCI) 179 (M−H⁺, 100%)

d) (1R-trans)-2-(4-Fluorophenyl)cyclopropanamine,[R—(R*,R*)]-2,3-dihydroxybutanedioate (1:1)

To a solution of the product from step c) (1.78 g) and triethylamine(2.7 ml) in acetone/water (10:1, 23 ml) at 0° C. was added ethylchloroformate (2.0 ml) over 5 min. The solution was maintained at 0° C.for 30 minutes before addition of sodium azide (1.52 g) in water (6 ml).After a further hour, water (350 ml) was added and the reaction mixtureextracted with toluene (3×100 ml). The organic extracts were combinedand dried, then heated at reflux for 2 hours behind a blast screen.After cooling the solution, 6N HCl (50 ml) was added and the mixtureheated at reflux for 3 hours. Water (150 ml) was added and the aqueousphase basified with 2N NaOH (aq), then extracted into dichloromethane(3×100 ml). The organic phase was dried and concentrated. The amine wasdissolved in ethanol (5 ml) and a solution of L-tartaric acid (1.48 g)in ethanol (20 ml) was added. After 20 minutes the solid was collectedaffording the subtitle compound as colourless needles (1.12 g).

NMR δH (d₆-DMSO) 1.07-1.39 (1H, m), 1.22-1.29 (1H, m), 2.16-2.23 (1H,m), 2.64-2.70 (1H, m), 3.95 (2H, s), 7.06-7.19 (4H, m)

e)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

N,N-Diisopropylethylamine (1.29 g) was added to a solution of[3aR-(3aα,4α,6α,6aα)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol(prepared as described in International Patent Application WO 9703084)(1.0 g) and the product of step d) (0.75 g) in dichloromethane (25 ml).The reaction mixture was stirred at room temperature for 3 hours, thenwashed with water, dried and evaporated. The residue was purified (SiO₂,ethyl acetate:isohexane 1:1 as eluent) to afford the subtitle compound(1.25 g).

MS (APCI) 515 (M+H⁺, 100%)

f)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

3-Chloroperoxybenzoic acid (70%, 1.8 g) was added to a suspension of theproduct of step e) (1.25 g) in ethanol (25 ml) and the resultingsolution stirred at room temperature for 2 hours. The reaction mixturewas concentrated and the residue taken up in ethyl acetate (500 ml),washed with 10% aqueous sodium metabisulfite solution (2×100 ml) and 10%aqueous sodium bicarbonate solution (2×100 ml) then dried andconcentrated to afford the subtitle compound (1.4 g).

MS (APCI) 547 (M+H⁺, 100%)

g)[[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

Sodium hydrosulfide hydrate (1.4 g) was added to a solution of theproduct of step f) (1.4 g) in dimethyl sulphoxide (20 ml) and thesolution stirred at room temperature for 1.5 hours. Brine (150 ml) wasadded and the mixture acidified with acetic acid then extracted withethyl acetate (3×100 ml). The organic phase was dried and concentratedand the residue azeotroped with toluene (3×100 ml). The residue wasdissolved in N,N-dimethylformamide (20 ml) thenN,N-diisopropylethylamine (0.33 g) and 3,3,3-trifluoropropylbromide(0.48 g) added. After stirring at 50° C. for 30 minutes the reactionmixture was diluted with ethyl acetate (100 ml) then washed with aqueousbrine (3×100 ml), dried and concentrated then the residue purified(SiO₂, isohexane:ethyl acetate 1:1 as eluant) to afford the subtitlecompound (1.4 g).

MS (APCI) 569 (M+H⁺, 100%)

h) [1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol

A solution of the product from step g) (1.4 g) in trifluoroacetic acid(10 ml) and water (2 ml) was stirred at room temperature for 1 hour. Thereaction mixture was diluted with ethyl acetate (400 ml) then washedwith sodium bicarbonate solution (400 ml), dried and evaporated. Theresidue was purified (SiO₂, methanol:chloroform 3:47 as eluant) toafford the title compound (0.44 g).

MS (APCI) 529 (M+H⁺, 100%)

NMR δH (d₆-DMSO) 9.42 (1H, d), 7.27-7.22 (2H, m), 7.14-7.08 (2H, m),5.01-4.95 (2H, m), 4.73-4.70 (2H, m), 4.44-4.41 (1H, m), 3.87-3.84 (1H,m), 3.50-3.45 (2H, m), 3.26-3.13 (3H, m), 2.60-2.55 (1H, m), 2.28-2.20(2H, m), 2.10-2.06 (1H, m), 1.90-1.80 (1H, m), 1.49-1.46 (1H, m),1.33-1.30 (1H, m).

Example 2[1R-[1α,2α,3β(1R*,2S*),5]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diola)[3aS-[1(E),3aα,6α,7aβ]]-1-[3-(3,4-Difluorophenyl)-1-oxo-2-propenyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

The subtitle compound was prepared according to the method of Example 1,step a) using 3-(3,4-difluorophenyl)-2-propenoic acid.

MS (APCI) 382 (M+H⁺, 100%)

b)[3aS-[1(1S*,2S*),3aα,6α,7aβ]]-1-[[2-(3,4-Difluorophenyl)cyclopropyl]carbonyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

The subtitle compound was prepared according to the method of Example 1,step b) using the product of step a).

MS (APCI) 396 (M+H⁺, 100%)

c) (1R-trans)-2-(3,4-Difluorophenyl)-cyclopropane carboxylic acid

The subtitle compound was prepared according to the method of Example 1,step c) using the product of step b).

NMR δH(CDCl₃) 7.06 (1H, dt. J=10.0, J=8.5 Hz), 6.93-6.80 (2H, m),2.58-2.52 (1H, m), 1.88-1.82 (1H, m), 1.66 (1H.dt, J=9.2, J=5.2 Hz),1.34 (1H, ddd, J=8.5, J=6.5, J=4.8 Hz).

d) (1R-trans)-2-(3,4-Difluorophenyl)cyclopropanamine,[R—(R*,R*)]-2,3-dihydroxybutanedioate (1:1)

The subtitle compound was prepared according to the method of Example 1,step d) using the product of step c).

MS (APCI) 170 (M+H⁺, 100%)

e)[3aR-[3aα,4α,6α(1R*,2S*),6aα]-6-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triaz[4,5-d]pyrimidin-3-yl]-triazolo-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

Isoamyl nitrite (5.1 ml) was added to a solution of[3aR-(3aα,4α,6α,6aα)]-6-[[5-amino-6-Chloro-2-[(3,3,3-trifluoropropyl)thio]-4-pyrimidinyl]-amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol(prepared as described in International Patent Application WO 9703084)(8.1 g) in acetonitrile (1000 ml) and the solution heated at 70° C. for1 hour. The cooled reaction mixture was concentrated and purified (SiO₂,dichloromethane:ethyl acetate 4:1 as eluant) to afford an intermediatewhich was converted to the subtitle compound by the method of example 1,step e) using the product of step d).

MS (APCI) 587 (M+H⁺, 100%)

f)[1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol

Prepared according to the method of example 1, step h) using the productof step e).

MS (APCI) 547 (M+H⁺, 100%)

NMR δH (d₆-DMSO) 9.43 (1H, d), 7.35-7.28 (2H, m), 7.14-7.02 (1H, m),5.01-4.96 (2H, m), 4.72-4.69 (2H, m), 4.42 (1H, q), 3.87-3.84 (1H, m),3.50-3.44 (2H, m), 3.25-3.12 (3H, m), 2.58-2.50 (2H, m), 2.28-2.21 (3H,m), 1.85-1.80 (1H, m), 1.52-1.50 (1H, m), 1.39-1.37 (1H, m).

Example 3[1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diola)(1R-cis)-Bis(1,1-dimethylethyl)-4-hydroxy-2-cyclopentenylimidodicarbonate

To a suspension of ether washed sodium hydride (60% dispersion in oil;0.31 g) in tetrahydrofuran (30 ml) was added imidodicarbonic acidbis-(1,1-dimethylethyl)ester (1.84 g). The mixture was stirred at 40° C.for 1 hour. To the mixture, at ambient temperature, was then added(1S-cis)-4-acetoxy-2-cyclopenten-1-ol (0.5 g) andtetrakis(triphenylphosphine)palladium(0) (0.18 g). The reaction mixturewas stirred for 24 hours then purified (SiO₂, ethyl acetate:hexane 1:9as eluant) to give the subtitle compound as a colourless solid (0.90 g).

NMR δH (d₆-DMSO) 1.43 (18H, s), 1.61 (1H, ddd, J=12.3, 7.7, 6.4 Hz),2.54 (1H, dt, J=12.6, 7.4 Hz), 4.51-4.57 (1H, m), 4.86 (1H, tq, J=8.0,1.8 Hz), 4.91 (1H, d, J=5.4 Hz), 5.71-5.77 (2H, m).

b) [1R-(1α.2β,3β,4α)]-2,3,4-Trihydroxy-cyclopentenylimidodicarbonicacid, bis(1,1-dimethylethyl)ester

To a solution of the product of step a) (17.1 g) in tetrahydrofuran (500ml)/water (50 ml) was added N-methylmorpholine-N-oxide (9.4 g) followedby osmium tetroxide (10 ml, 2.5% solution in r-butanol). The mixture wasstirred at room temperature for 4 days then treated with sodiumhydrosulphite (6.0 g). The suspension was filtered through celite andthe product purified (SiO₂, ethyl acetate:hexane 1:1 as eluant) toafford the subtitle compound (19.1 g).

NMR δH (d₆-DMSO) 1.44 (18H, s), 1.46-1.60 (1H, m), 1.97-2.05 (1H, m),3.55-3.58 (1H, m), 3.66-3.73 (1H, m), 4.11-4.21 (2H, m), 4.54 (1H, d,J=4.8 Hz), 4.56 (1H, d, J=5.9 Hz), 4.82 (1H, d. J=4.6 Hz)

c)[3aR-(3aα,4α,6α,6aα)]-6-Amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol,hydrochloride

The product from step b) (17.4 g) in 6M HCl (100 ml)/methanol (500 ml)was stirred for 18 hours. The mixture was evaporated and then azeotropedwith toluene (4×200 ml) to give a colourless powder (8.7 g). This solidwas suspended in acetone (250 ml) containing 2,2-dimethoxypropane (25ml) and cHCl (0.2 ml) then heated under reflux for 2 hours. The mixturewas cooled, evaporated and azeotroped with toluene (3×200 ml). Theresidue was dissolved in 20% aqueous acetic acid and stirred for 2hours. The mixture was evaporated and azeotroped with toluene (4×200 ml)to afford the subtitle compound (10.1 g).

MS (APCI) 174 (M+H⁺, 100%)

d)[3aR-(3aα,4α,6aα)]-6-[[6-Chloro-5-nitro-2-(propylthio)-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

A solution of the product from step c) (10.0 g) andN,N-diisopropylethylamine (35 ml) in tetrahydrofuran (600 ml) wasstirred for 1 hour. The mixture was filtered and the solution was addedover 1 hour to a solution of4,6-dichloro-5-nitro-2-(propylthio)-pyrimidine (prepared as described inInternational Patent Application WO 9703084) (25.6 g) in tetrahydrofuran(1000 ml) and stirred for a further 2 hours. The solvent volume wasreduced in vacuo and ethyl acetate was added (1000 ml). The mixture waswashed with water and the organic layers were dried, evaporated andpurified (SiO₂, isohexane-ethyl acetate as eluant) to afford thesubtitle compound (14.2 g).

MS (APCI) 405 (M+H⁺, 100%)

e)[3aR-(3aα,4α,6α,6aα)]-6-[[5-Amino-6-Chloro-2-(propylthio)-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

Iron powder (3.0 g) was added to a stirred solution of the product ofstep d) (2.7 g) in acetic acid (100 ml). The reaction mixture wasstirred at room temperature for 2 hours, concentrated to half volume,diluted with ethyl acetate and washed with water. The organic phase wasdried and concentrated to afford the subtitle compound (2.0 g).

MS (APCI) 375 (M+H⁺, 100%)

f)[3aR-(3aα,4α,6α,6aα)]-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

Isoamyl nitrite (1.1 ml) was added to a solution of the product of stepe) (2.0 g) in acetonitrile (100 ml) and the solution heated at 70° C.for 1 hour. The cooled reaction mixture was concentrated and purified(SiO₂, ethyl acetate:isohexane 1:3 as eluant) to afford the subtitlecompound (1.9 g).

MS (APCI) 386 (M+H⁺, 100%)

g) [3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

The product of step f) (13.2 g) in tetrahydrofuran (200 ml) containing0.88 ammonia (5 ml) was stirred for 2 hours then concentrated to drynessand the residue partitioned between water and ethyl acetate. Theorganics were dried and then concentrated to afford the subtitlecompound (12.5 g).

MS (APCI) 367 (M+H⁺, 100%).

h)[3aR-(3aα,4α,6α,6aα)]-[[6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,S-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]aceticacid, methyl ester

To a solution of the product of step g) (0.50 g) in tetrahydrofuran (25ml) at 0° C., was added butyllithium (0.62 ml of 2.5N in hexanes). After20 minutes, the suspension was treated with a solution oftrifluoromethanesulfonyloxy-acetic acid methyl ester (0.34 g) (preparedaccording to the method of Biton, Tetrahedron, 1995, 51, 10513) intetrahydrofuran (10 ml). The resulting solution was allowed to warm toroom temperature then concentrated and purified (SiO₂, ethylacetate:hexane 4:6 as eluant) to afford the subtitle compound (0.25 g).

MS (APCI) 439 (M+H⁺, 100%).

i)[3aR-(3aα,4α,6α,6aα)]-[[6-[7-Bromo-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]aceticacid, methyl ester

The product from step h) (1.1 g) and isoamylnitrite (2.4 ml) inbromoform (30 ml) was heated at 80° C. for 30 minutes. The cooledreaction mixture was purified (SiO₂, ethyl acetate:isohexane 1:4 aseluant) to afford the subtitle compound (0.44 g).

MS (APCI) 502/4 (M+H⁺), 504 (100%).

j)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-[[6-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]aceticacid, methyl ester

To a mixture of the products from step i) (0.80 g) and Example 2, stepd) (0.61 g) in dichloromethane (25 ml) was addedN,N-diisopropylethylamine (0.85 ml). The resulting solution was stirredat room temperature for 16 hours then concentrated in vacuo.Purification (SiO₂, isohexane:ethylacetate 3:1 as eluant) gave thesubtitle compound as a colourless foam (0.77 g).

MS (APCI) 591 (M−H⁺, 100%)

k)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-2-[6-[[7-[2-(3,4-Difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol

DIBAL-H® (1.0M solution in hexanes, 5.15 ml) was added to an ice-cooledsolution of the product of step j) (0.76 g) in tetrahydrofuran (1 ml)and the solution stirred at this temperature for 2 hours. The reactionmixture was concentrated in vacuo and the residue was dissolved in ethylacetate (75 ml). A saturated aqueous solution of sodium potassiumtartrate (75 ml) was added and the mixture stirred vigorously for 16hours. The organics were collected and the aqueous re-extracted withethyl acetate (2×50 ml). The combined organics were dried andconcentrated and the residue purified (SiO₂, isohexane:ethylacetate 1:1as eluant) to give the subtitle compound (0.63 g).

MS (APCI) 563 (M+H⁻, 100%)

l)[1S-[1α,2α,3β(1S*,2R*),5β]]-3-[7-(2-(3,4-Difluorophenyl)cyclopropyamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol

Prepared according to the method of example 1, step h) using the productof step k).

MS (APCI) 523 (M+H⁺, 100%)

NMR δH (d₆-DMSO) 8.95 (1H, d, J=3.3 Hz), 7.39-7.21 (2H, m), 7.10-7.00(1H, m), 5.12 (1H, d, J=6.4 Hz), 5.05 (1H, d, J=3.6 Hz), 4.96 (1H, q,J=9.0 Hz), 4.62-4.54 (2H, m), 3.95 (1H, br s), 3.79-3.73 (1H, m),3.55-3.47 (4H, m), 3.20-3.13 (1H, m), 2.98-2.81 (2H, m), 2.63 (1H, dt.J=13.6, 8.5 Hz), 2.29-2.21 and 2.16-2.09 (1H, m), 2.07-2.00 (1H, m),1.73-1.33 (4H, m), 0.99 (3H, t, J=7.4 Hz).

Example 4[1R-[1α,2α,3β(1R*,2S*),5β]]-3-[S-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diola)[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

Prepared according to the method of Example 3, step g) using[3aR-(3aα,4α,6α,6aα)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol(prepared as described in International Patent Application WO 9703084).The crude product was purified (SiO₂, methanol:dichloromethane 1:19 aseluant) to give the subtitle compound.

MS (APCI) 381 (M+H⁺, 100%).

b)[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

Prepared according to the method of example 1, step f) using the productof step a).

MS (APCI) 413 (M+H⁺, 100%).

c)[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-3-(butylthio)-3H-1,2,3-triazolo[4,S-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

1-Butanethiol (2.38 ml) in DMF (25 ml) was added to a suspension ofsodium hydride (60%, 1.09 g) in DMF (50 ml). After 1 hour a solution ofthe product of step b) (3.66 g) in DMF (65 ml) was added dropwise andthe resulting mixture was stirred overnight. The reaction mixture wasadded slowly to saturated aqueous sodium bicarbonate (1000 ml) and thenis extracted into ethyl acetate (3×200 ml). The organic phase was dried(MgSO₄) and concentrated in vacuo and the residue purified (SiO₂,methanol:dichloromethane 1:19 as eluant) to give the subtitle compound(3.32 g).

MS (APCI) 395 (M+H⁺, 100%).

d)[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol,acetate

To a solution of the product from step c) (3.3 g) in dichloromethane (50ml), was added pyridine (2.7 ml), 4-dimethylaminopyridine (0.4 g) andacetic anhydride (2.0 ml). The mixture was stirred at room temperatureovernight, concentrated in-vacuo and purified (SiO₂, diethylether:isohexane 3:2 as eluent) to give the subtitle compound (2.7 g).

MS (APCI) 437 (M+H⁺, 100%).

e)[3aR-(3aα,4α,6α,6aα)]-6-[7-Bromo-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol,acetate

Prepared according to the method of example 3, step i) using the productof step d).

MS (APCI) 500/502 (M+H⁻), 500 (100%).

f)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol,acetate

Prepared according to the method of example 3, step j) using the productof example 2, step d) and the product of step e).

MS (APCI) 589 (M+H⁺, 100%).

g)[1R-[1α,2α,3β(1R*,2S*),5β]]-3-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol

The product of step f) (0.64 g) in 80% aqueous acetic acid (30 ml) washeated at 80° C. for 1 hour. The cooled mixture was poured intosaturated sodium bicarbonate solution and extracted into ethyl acetate.The organic phase was dried and concentrated in vacuo to give a gumwhich was dissolved in methanol (50 ml)/10% aqueous potassium carbonatesolution (3 ml). The solution was stirred for 30 minutes, neutralisedwith acetic acid, and concentrated in vacuo. Purification (SiO₂,methanol:dichloromethane 1:19 as eluent) gave a solid which wasrecrystallised (acetonitrile) to give the title compound (0.25 g).

MS (APCI) 507 (M+H⁺, 100%).

NMR δH (d₆-DMSO) 9.34 (1H, br), 7.40-7.23 (2H, m), 7.11-7.00 (1H, m),5.06-4.93 (2H, m), 4.76-4.67 (2H, m), 4.48-4.38 (1H, m), 3.91-3.84 (1H,m), 3.56-3.39 (2H, m), 3.21-3.08 (1H, m), 3.03-2.83 (2H, m), 2.32-2.17(1H, m), 2.17-2.03 (2H, m), 1.91-1.77 (1H, m), 1.71-1.32 (4H, m),1.32-1.17 (2H, m), 0.81 (3H, t).

Example 5[1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(4-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,d]pyrimidin-3-yl]-cyclopentane-1,2,3-triola) [3aR-[3aα,4α,6α,6aα(1S*,2R*)]]-6-[7-[[(4-Fluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

Prepared according to the method of example 1, step e) using the productof example 1, step d) and the product of example 3 step f).

MS (APCI) 501 (M+H⁺, 100%).

b) [3aR-[3aα,4α,6α,6aα(1S*,2R*)]]-6-[[7-[(4-Fluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

Prepared according to the method of example 1, step f) using the productof step a).

MS (APCI) 532 (M+H⁺, 100%).

c)[3aR-[3aα,4α,6α,6aα(1S*,2R*)]]-6-[7-[[(4-Fluorophenyl)cyclopropyl]amino]-5-(butylthio)-3H-1,2,3-triazolo[4,-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

Prepared according to the method of example 4 step c) using the productof step b).

MS (APCI) 515 (M+H⁺, 100%).

[1S-[1α,2β,3β,4α(1S*,2*)]]-4-[5-(Butylthio)-7-[[2-(4-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2,3-triol

Prepared according to the method of example 1 step h) using the productof step c).

MS (APCI) 575 (M+H⁺, 100%).

NMR δH (d₆-DMSO) 7.26-7.22 (2H, m), 7.11 (2H, t), 4.99-4.90 (1H, m),4.67-4.63 (1H, m), 3.93 (1H, s), 3.77 (1H, bs), 3.35-3.13 (1H, m),3.00-2.80 (2H, m), 2.59-2.51 (1H, m), 2.15-2.11 (1H, m), 1.91-1.86 (1H,m), 1.53-1.41 (3H, m), 1.35-1.30 (1H, m), 1.22 (2H, sex), 0.80 (3H, t).

Example 6[1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diola)[1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol

The subtitle compound was prepared according to the method of Example 1,step f) using the product of Example 3, step 1.

MS (APCI) 555 (M+H⁺, 100%)

b)[1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol

The title compound was prepared according to the method of Example 1,step g) using the product of step a).

MS (APCI) 555 (M+H⁺, 100%)

NMR δH (d₆-DMSO) 9.45 (1H, d), 7.36-7.05 (3H, m), 5.05 (1H, d), 5.02(1H, d), 4.95 (1H, m), 4.60 (2H, m), 3.95 (1H, m), 3.86 (1H, m), 3.47(4H, m), 3.30-3.11 (3H, m), 2.63-2.49 (3H, m), 2.19 (1H, m), 2.00 (1H,m), 1.53 (1H, m), 1.40 (1H, m).

Example 7[1S-[1α,2α,3β,5β(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-(2-phenylcyclopropyl)amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diola)(1S-cis)-2-[[4-[[6-Chloro-5-nitro-2-[(3,3,3-trifluoropropyl)thio]-4-pyrimidinyl]amino]-2-cyclopenten-1-yl]oxy]-aceticacid, ethyl ester

A solution of sodium azide (4.70 g) in degassed water (25 ml) was addedto a solution of (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate (9.99 g)in tetrahydrofuran (60 ml) and stirred for 10 min.Tetrakis(triphenylphosphine)palladium(0) (365 mg) was added and stirredfor min. The aqueous layer was separated and extracted twice with ethylacetate. The combined organic layers were dried (MgSO₄), concentratedand purified on a short column (SiO₂, ethyl acetate:isohexane 1:2 aseluant) to afford a yellow oil. This was dissolved in tetrahydrofuran(25 ml) and slowly added to a suspension of sodium hydride (2.94 g, 60%dispersion in oil) in tetrahydrofuran (60 ml) at −78° C. A solution ofethyl bromoacetate (8.2 ml) in tetrahydrofuran (5 ml) was added and themixture was allowed to warm to 20° C. and stirred for 30 min. Aqueousammonium chloride solution was added and the mixture was extracted withether. The organic layers were dried (MgSO₄), concentrated and purified(SiO₂, ether:isohexane 1:5 as eluant) to afford a colourless oil. Asolution of this oil and triphenylphosphine (17.89 g) in tetrahydrofuran(90 ml) was stirred for 10 min. Water (15 ml) was added and the solutionwas stirred for 18 hours. The solvent was removed in vacuo and theresidue azeotroped with toluene then purified (SiO₂, ethyl acetate thenethyl acetate-methanol-ammonia (90:9:1) as eluant) to afford a paleyellow oil (7.14 g).

A solution of this compound in tetrahydrofuran (50 ml) was added over 25min to a solution of4,6-dichloro-5-nitro-2-[(3,3,3-trifluoropropyl)thio]pyrimidine (preparedas described in International Patent Application WO 9703084) (24.8 g)and N,N-diisopropylethylamine (77.5 ml) in dry tetrahydrofuran (100 ml)and then stirred for 30 minutes. Water was added and the mixture wasextracted with ether (three times). The organic layers were dried(MgSO₄), concentrated and purified (SiO₂, ethyl acetate:isohexane 1:4 aseluant) to afford the subtitle compound (7.39 g).

MS (APCI) 367/9 (M−(EtO₂CCH₂O)⁺), 367 (100%)

b) (1S-cis)2-[[4-[7-Chloro-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-aceticacid, ethyl ester

Prepared according to the method of example 3, steps e) and f) using theproduct of step a).

MS (APCI) 348/50 (M−(EtO₂CCH₂O)⁺), 348 (100%).

c)[1S-(cis)]2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-aceticacid, ethyl ester

Prepared according to the method of example 3, step g) using the productof step b).

MS (APCI) 433 (M+H⁻, 100%).

d)[1S-(cis)]2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-1-ethanol

Prepared according to the method of example 3, step k) using the productof step c).

MS (APCI) 391 (M+H⁻, 100%).

e)[3aR-(3aα,4α,6α,6aα)]-2-[6-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy]ethanol

A solution of the product from step d) (454 mg), osmium tetroxide (0.17ml of 0.1 M solution in t-butanol), N-methylmorpholine N-oxide (2.10 mg)and pyridine (0.09 ml) in acetone (5 ml) and water (1 ml) was heated at70° C. for 5 hours. Sodium hydrosulfite (330 mg) in water (1 ml) wasadded, the solvent was remove in vacuo and the residue azeotroped withtoluene. A solution of this and p-toluenesulfonic acid (50 mg) inacetone (5 ml) and 2,2-dimethoxypropane (2 ml) was stirred for 3 h. Thesolvent was remove in vacuo, aq sodium hydrogen carbonate solution addedand the mixture was extracted with ethyl acetate. The organic layerswere dried (MgSO₄), concentrated and purified (SiO₂,isohexane:acetone5:2 as eluant) to afford the subtitle compound as a white solid (367mg).

MS (APCI) 465 (M+H⁻, 100%)

f)[3aR-(3aα,4α,6α,6aα)]-2-[6-[7-Bromo-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy]ethanol

Prepared according to the method of Example 3, step i) using the productof step e).

MS (APCI) 528/30 (M+H⁻), 528 (100%)

g)[3aR-[3aα,4α,6α(1R*,2S*),6aα]-2-[6-(7-Phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-1,3-dioxol-4-yloxy]ethanol

Prepared according to the method of Example 3, step j) using the productof step f) and (1R-trans)-2-phenyl-cyclopropanamine,[R—(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described by L.A. Mitscher et al., J. Med. Chem. 1986, 29, 2044).

MS (APCI) 581 (M+H⁺, 100%)

h) [1S-[1α,2α,3β,5β(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-(2-phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol

Prepared according to the method of Example 1, step h) using the productof step g).

MS (APCI) 540 (M+H⁺, 100%).

NMR δH (d_(b)-DMSO) 7.35-7.16 (5H, m), 4.97 (1H, q), 4.62-4.54 (1H, m),3.98-3.92 (1H, m), 3.78-3.72 (1H, m), 3.55-3.44 (4H, m), 3.26-3.19 (2H,m), 3.16-3.07 (1H, m), 2.70-2.61 (1H, m), 2.58-2.52 (1H, m), 2.23-2.18(1H, m), 2.05-1.97 (1H, m), 1.86 (1H, s), 1.54-1.46 (1H, m), 1.38-1.30(1H, m).

Example 8[1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triola)[3aR-[3aα,4α,6α(1R*,2S*),6aα]-6-[[7-[(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

The subtitle compound was prepared according to the method of Example 1,step e) using the product of Example 3, step f) and the product ofexample 2, step d).

MS (APCI) 519 (M±H⁺, 100%).

b)[3aR-[3aα;4α,6α(1R*,2S*),6α]]-6-[[7-[(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

The subtitle compound was prepared according to the method of Example 1,step f) using the product of step a).

MS (APCI) 551 (M+H⁺, 100%).

c)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

The subtitle compound was prepared according to the method of Example 4,step c) using the product of step b).

MS (APCI) 533 (M+H⁺, 100%)

d)[1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol

The title compound was prepared according to the method of Example 1,step h) using the product of step c).

NMR δH (d₆-DMSO) 7.15-6.98 (3H, m), 6.67 (1H, s), 5.11-5.09 (1H, m),4.82-4.76 (1H, m), 4.34-4.21 (3H, m), 3.7 (1H, s), 3.2-2.92 (4H, m),2.77 (1H, m), 2.42-2.36 (1H, m), 2.2-2.18 (1H, m), 1.42-1.25 (6H, m),0.9 (3H, q).

MS (APCI) 493 (M±+H⁺, 100%)

Example 9[1S-[1aα,2α,3β(1S*,2R*),5β]]-3-[5-(Butylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxethoxy)-cyclopentane-1,2-diola)[3aS-(3aα,4α,6α,6aα)]-[Tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamicacid, phenylmethyl ester

Potassium carbonate (39.3 g) was added to a suspension of[3aR-(3aα,4α,6α,6aα)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol,hydrochloride, (prepared as described in WO 9905142) (27.1 g) in4-methyl-2-pentanone (500 ml). Water (150 ml) was then added followed bydropwise addition of benzyl chloroformate (23.1 g). The reaction mixturewas stirred at room temperature for 4 hours before the organic phase wasseparated. The aqueous phase was extracted with 4-methyl-2-pentanone(2×50 ml). The combined organics were concentrated and the residue waspurified (SiO₂, dichloromethane:methanol, 95:5 to 90:10 as eluant) togive the subtitle compound (39.23 g).

NMR δH (CDCl₃) 7.32 (5H, m), 5.65 (1H, br s), 5.10 (2H, br s), 4.59 (1H,d), 4.48 (1H, d), 4.27 (1H, m), 4.19 (1H, br m), 2.24 (1H, br s), 1.69(1H, d), 1.41 (3H, s), 1.26 (3H, s).

b)[3aS-(3aα,4α,6α,6aα)]-[2,2-Dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamicacid, phenylmethyl ester

Potassium tert-butoxide (3.6 g) in tetrahydrofuran (20 ml) was addedover 5 minutes to a solution of the product from step a) (39.23 g) intetrahydrofuran (200 ml). After 15 minutes, ethyl bromoacetate (3.7 ml)in tetrahydrofuran (10 ml) was added dropwise. The mixture to wasstirred at 0° C. for 10 minutes, then further ethyl bromoacetate wasadded (3.7 ml×4). The reaction mixture was stirred at 0° C. a further 2hours. Lithium borohydride (2.79 g) was then added portionwise to theresulting suspension and the reaction mixture was stirred at <5° C. for16 hours. Glacial acetic acid (23 g) was added dropwise to the coldmixture. After stirring for 30 minutes, water (100 ml) was addeddropwise and the resulting mixture was stirred for 30 minutes. Thephases were then separated and the aqueous phase was extracted withethyl acetate. The combined organics were washed with saturated sodiumbicarbonate and brine, dried and concentrated. The residue was purified(SiO₂, ethyl acetate:hexane, 25:75 to 50:50 as eluant) to give thesubtitle compound (38.6 g).

MS (APCI) 218 (M+H⁺, 100%).

c))[3aR-(3aα,4α,6α,6aα)]-2-[[6-Amino-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol

A slurry of 5% palladium on charcoal (4 g) in ethanol was added to asolution of the product from step b) (39.96 g) in ethanol (250 ml) andthe mixture was hydrogenated at 1.2 bar for 20 hours. The catalyst wasfiltered off and the filtrate was concentrated to give the subtitlecompound (23.65 g).

MS (APCI) 160 (M+H⁺, 100%).

d) 2-(Butylthio)-4,6-dichloropyrimidine-5-amine

The subtitle compound was prepared according to the method of example 3,step e) using 2-(butylthio)-4,6-dichloro-5-nitro-pyrimidine (prepared asdescribed in DE 2223644).

NMR δH (CDCl₃) 4.20 (2H, br s), 3.10 (2H, t), 1.70 (2H, m), 1.47 (2H,m), 0.95 (3H, t).

e)[3aR-(3aα,4α,6α,6aα)]-2-[[6-[[5-Amino-2-(butylthio)-6-chloro-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]ethanol

The subtitle compound was prepared according to the method of example 3,step d) using the products of steps c) and d).

MS (APCI) 433 (M+H⁺, 100%).

f)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-2-[6-[[5-(Butylthio)-7-chloro-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol

The subtitle compound was prepared according to the method of Example 3,step f) using the product of step e).

NMR δH (CDCl₃) 5.53 (1H, m), 5.21 (1H, m), 4.88 (1H, d), 4.05 (1H, m),3.59 (4H, m), 3.24 (2H, t), 2.70 (1H, m), 2.53 (1H, m), 2.13 (1H, t),1.79 (2H, m), 1.55 (5H, m), 1.37 (3H, s), 0.98 (3H, t).

g)[3aR-[3aα,4α,6α(R*,2S*),6aα]]-2-[6-[[5-(Butylthio)-7-[2-phenylcyclopropyl]amino-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol

The subtitle compound was prepared according to the method of Example 3,step j) using the product of step f).

MS (APCI) 541 (M+H⁺, 100%).

h)[1S-[1α,2α,3β(1S*,2R*),5β]]-3-[5-(Butylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxethoxy)-cyclopentane-1,2-diol

The title compound was prepared according to the method of example 1,step h) using the product of step g).

MS (APCI) 501 (M+H⁺, 100%)

NMR δH (d₆-DMSO) 9.33 (1H, d), 7.30 (2H, m), 7.18 (3H, m), 5.12 (1H, d),5.04 (1H, d), 4.96 (1H, q), 4.59 (2H, m), 3.94 (1H, s), 3.76 (1H, m),3.51 (4H, m), 3.22 (1H, m), 2.98 (1H, m), 2.86 (1H, m), 2.65 (1H, m),2.14 (1H, m), 2.05 (1H, m), 1.21-1.53 (6H, m), 0.80 (3H, t).

Pharmacological Data

The preparation for the assay of the P_(2T) (P2Y_(ADP) or P2T_(AC))receptor agonist/antagonist activity in washed human platelets for thecompounds of the invention was carried out as follows.

Human venous blood (100 ml) was divided equally between 3 tubes, eachcontaining 3.2% trisodium citrate (4 ml) as anti-coagulant. The tubeswere centrifuged for 15 minutes at 240G to obtain a platelet-rich plasma(PRP) to which 300 ng/ml prostacyclin was added to stabilize theplatelets during the washing procedure. Red cell free PRP was obtainedby centrifugation for 10 minutes at 125G followed by furthercentrifugation for 15 minutes at 640G. The supernatant was discarded andthe platelet pellet resuspended in modified, Calcium Free Tyrodesolution (10 ml) (CFT), composition: NaCl 137 mM, NaHCO₃ 11.9 mM,NaH₂PO₄ 0.4 mM, KCl 2.7 mM, MgCl₂ 1.1 mM, dextrose 5.6 mM, gassed with95% O₂/5% CO₂ and maintained at 37° C. Following addition of a further300 ng/ml PGI₂, the pooled suspension was centrifuged once more for 15minutes at 640G. The supernatant was discarded and the plateletsresuspended initially in 10 ml CFT with further CFT added to adjust thefinal platelet count to 2×10⁵/ml. This final suspension was stored in a60 ml syringe at 3° C. with air excluded. To allow recovery fromPGI-inhibition of normal function, platelets were used in aggregationstudies no sooner than 2 hours after final resuspension.

In all studies, 3 ml aliquots of platelet suspension were added to tubescontaining CaCl₂ solution (60 μl of 50 mM solution with a finalconcentration of 1 mM). Human fibrinogen (Sigma, F 4883) and8-sulphophenyltheophylline (8-SPT which was used to block any P₁-agonistactivity of compounds) were added to give final concentrations of 0.2mg/ml (60 μl of 10 mg/ml solution of clottable protein in saline) and300 nM (10 μl of 15 mM solution in 6% glucose), respectively. Plateletsor buffer as appropriate were added in a volume of 150 μl to theindividual wells of a 96 well plate. All measurements were made intriplicate in platelets from each donor.

The agonist/antagonist potency was assessed as follows.

Aggregation responses in 96 well plates were measured using the changein absorbance given by the plate reader at 660 nm. Either a Bio-TecCeres 900C or a Dynatech MRX were used as the plate reader.

The absorbance of each well in the plate was read at 660 nm to establisha baseline figure. Saline or the appropriate solution of test compoundwas added to each well in a volume of 10 μl to give a finalconcentration of 0.0.01, 0.1, 1, 10 or 100 mM. The plate was then shakenfor 5 min on an orbital shaker on setting 10 and the absorbance read at660 nm. Aggregation at this point was indicative of agonist activity ofthe test compound. Saline or ADP (30 mM; 10 μl of 450 mM) was then addedto each well and the plate shaken for a further 5 min before reading theabsorbance again at 660 nm.

Antagonist potency was estimated as a % inhibition of the control ADPresponse to obtain an IC₅₀. Compounds exemplified have pIC₅₀ values ofmore than 5.0.

1. A compound of formula (I)

wherein: R¹ is C₃₋₅ alkyl optionally substituted by one or more halogen atoms; R² is a phenyl group, optionally substituted by one or more fluorine atoms; R³ and R⁴ are both hydroxy; R is XOH, where X is CH₂, OCH₂CH₂ or a bond; or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt provided that: when X is CH₂ or a bond, R¹ is not propyl, when X is CH₂ and R¹ is CH₂CH₂ CF₃, butyl or pentyl, the phenyl group at R² must be substituted by fluorine, when X is OCH₂CH₂ and R¹ is propyl, the phenyl group at R² must be substituted by fluorine.
 2. A compound according to claim 1 in which R¹ is 3,3,3,-trifluoropropyl, butyl or propyl.
 3. A compound according to claim 1 in which R² is phenyl or 4-fluorophenyl or 3,4-difluorophenyl.
 4. A compound according to claim 1 in which R is CH₂OH or OCH₂CH₂ OH.
 5. A compound according to claim 1 which is: [1R-[α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol: [1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol; [1S-(1α,2α,3β(1S*,2R*),5]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol; [1R-[1α,2α,3β(1R*,2S*),5p]]-3-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol; [1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(4-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2,3-triol; [1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol; [1S-[1α,2α,3β,5β(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-(2-phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol [1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2(3,4-difluorophenyl)cyclopropyl]-amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol; [1S-[1α,2α,3β(1S*,2R*),5]]-3-[5-(Butylthio)-7-[(2-phenylcylopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxethoxy)-cyclopentane-1,2-diol; or pharmaceutically acceptable salts or solvates thereof, or solvates of such salts.
 6. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable diluent, adjuvant and/or carrier.
 7. A pharmaceutical composition comprising a compound according to claim 1 for use in the treatment or prevention of myocardial infarction, thrombotic stroke, transient ischaemic attacks, and/or peripheral vascular disease.
 8. A pharmaceutical composition comprising a compound according to claim 1 for use in the treatment or prevention of unstable or stable angina.
 9. A compound according to claim 1 for use in therapy.
 10. A compound according to claim 1 for use in the treatment or prevention of myocardial infarction, thrombotic stroke, transient ischaemic attacks, and/or peripheral vascular disease.
 11. A compound according to claim 1 for use in the treatment or prevention of unstable or stable angina.
 12. The use of a compound according to claim 1 as an active ingredient in the manufacture of a medicament for use in the treatment or prevention of myocardial infarction, thrombotic stroke, transient ischaemic attacks, and/or peripheral vascular disease.
 13. The use of a compound according to claim 1 as an active ingredient in the manufacture of a medicament for use in the treatment or prevention of unstable or stable angina.
 14. A method of treatment or prevention of a platelet aggregation disorder which comprises administering to a person suffering from or susceptible to such a disorder a therapeutically effective amount of a compound according to claim
 1. 15. A method of treatment or prevention of myocardial infarction, thrombotic stroke, transient ischaemic attacks, and/or peripheral vascular disease, which comprises administering to a person suffering from or susceptible to such a condition a therapeutically effective amount of a compound according to claim
 1. 16. A method of treatment or prevention of unstable or stable angina which comprises administering to a person suffering from or susceptible to such a condition a therapeutically effective amount of a compound according to claim
 1. 17. A process for the preparation of a compound of formula (I) which comprises reacting a compound of formula (II):

where R, R¹, R³ and R⁴ are as defined in claim 1, or are protected derivatives thereof, or R³ and R⁴ together form a bond in the 5-membered ring, or R is CH₂CH₂ OR where R is C₁₋₆alkyl or benzyl, and L is a leaving group, with a compound of formula (III):

where R² is defined in claim 1 or is a protected derivative thereof, in the presence of a base in an inert solvent at ambient or elevated temperature, and optionally thereafter and in any order: converting one or more functional groups into further functional groups; removing any protecting groups: forming a pharmaceutically acceptable salt or solvate, or a solvate of such a salt.
 18. The compounds: [3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol: [[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol; [3aR-[3aα,4α,6α(1R*,2S*),6aα]-6-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol; [3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol; [3aR-(3aα,4α,6α,6aα)]-[[6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]acetic acid, methyl ester; [3aR-(3aα,4α,6α,6aα)]-[[6-[7-Bromo-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]acetic acid, methyl ester; [3aR-[3aα,4α,6α(1R*,2S*),6aα]]-[[6-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]acetic acid, methyl ester; [3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[[7-[2-(3,4-Difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol; [3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol; [3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol: [3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol; [3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol, acetate; [3aR-[3aα,4α,6α,6aα)]-6-[7-Bromo-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol, acetate; [3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol, acetate; [3aR-[3aα,4α,6α,6aα(1S*,2R*)]]-6-[7-[[(4-Fluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol; [3aR-[3aα,4α,6α,6aα(1S*,2R*)]]-6-[[7-[(4-Fluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol; [3aR-[3aα,4α,6α,6aα(1S*,2R*)]]-6-[7-[[(4-Fluorophenyl)cyclopropyl]amino]-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol; [1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol; (1S-cis)-2-[[4-[[6-Chloro-5-nitro-2-[(3,3,3-trifluoropropyl)thio]-4-pyrimidinyl]amino]-2-cyclopenten-1-yl]oxy]-acetic acid, ethyl ester; (1S-cis)2-[[4-[7-Chloro-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-acetic acid, ethyl ester; [1S-(cis)]2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-acetic acid, ethyl ester; [1S-(cis)]2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thiol-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy-1-ethanol; [3aR-(3aα,4α,6α,6aα)]-2-[6-[7-Amino-5-[(3,3,3-trifluoropropyl)thiol-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy]ethanol; [3aR-(3aα,4α,6α,6aα)]-2-[6-[7-Bromo-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo]-4-yloxy]ethanol; [3aR-[3aα,4α,6α(1R*2S*),6aα]-2-[6-(7-Phenylcyclopropyl)amino]5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-1,3-dioxol-4-yloxy]ethanol; [3aR-[3aα,4α,6α(1R*2S*),6aα-6-[[7-[(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol; [3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[[7-[(3,4-Difluorophenyl)cyclopropyl]aminol-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol; [3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol; [3aS-(3aα,4α,6α,6aα)]-[Tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid, phenylmethyl ester; [3aS-(3aα,4α,6α,6aα)-[2,2-Dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid, phenylmethyl ester; [3aR-(3aα,4α,6α,6aα)-2-[[6-Amino-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol; 2-(Butylthio)-4,6-dichloropyrimidine-5-amine; [3aR-(3aα,4α,6α,6aα)]-2-[[6-[[5-Amino-2-(butylthio)-6-chloro-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]ethanol; [3aR-[3aα,4α,6α(1R*,2S*),6aα]]-2-[6-[[5-(Butylthio)-7-chloro-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol; [3aR-[3aα,4α,6α(1R*,2S*),6aα]]-2-[6-[[5-(Butylthio)-7-[2-phenylcyclopropyl]amino-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol. 